Diabetes Mellitus Type II: Treatment Strategies and Options: A Review

Type II diabetes mellitus is a clinical syndrome due to relative or absolute deficiency of insulin or resistance to the action of insulin at the cellular level as a result hyperglycemia and glycosuria occurs [1]. Various new therapies have been introduced such as inhibition of enzymes that are involved in hydrolysis of dietary polysaccharides in the gut which can lead to reduction in blood glucose levels after a meal by reducing the absorption of monosaccharide by the entrecotes of the small intestine. Enzymes that are involved in hydrolysis of dietary polysaccharides are pancreatic amylase and glycosidase. With the advancement in treatment strategy there is risk of side effect such as excessive inhibition of pancreatic amylase may lead to abdominal distention, flatulence and diarrhea. Currently available therapies for type II diabetes mellitus are as follows oral insulin secretagogues, sulfonylureas, repaglinide, nateglinide, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, insulin, pramlintide and exenatide. Oral hypoglycemic drugs are valuable in the treatment of patients with type II diabetes mellitus (NIDDM). Sulphonylureas and biguanides are traditional drugs which are mainstay of treatment while there are certain new drugs available now [2,3]. Insulin is used as hypoglycemic agent in Type II diabetes mellitus [4]. The use of herbal medicines (medicinal plants or phytotherapy) has recently gained popularity in all over the world for their efficacy in Type II diabetes mellitus (Table 1) and some plants have minor side effects when given in large doses (Table 2). But there is lack of understanding the actual mechanism of action of these medicines. These medicines are used since centuries in Unani system of medicine and they have more efficacy and fewer or no side effects therefore emphasis should be given on herbal medicine because allopathic system of medicine has failed in providing health to all. Herbal medicines are only alternative medicine that can relieve the patients. Various research studies have been carried in all over the world to evaluate the efficacy of herbs in the treatment of Type II diabetes mellitus [5]. Medicinal plants have been used for the treatment of type II diabetes mellitus since ancient times, and for a long time type II diabetes mellitus has been treated orally with herbal medicines or their extracts, because plant products are frequently prescribed due to their less toxicity than conventional medicines. Shanmugam et al. reported medicinal plants used for the treatment of type II diabetes mellitus [6]. Type II diabetes mellitus is associated with disturbances in learning, memory, and cognitive skills in the diabetic patients. A study was conducted to evaluate the effect of chronic intraperitoneal administration of Apium graveolens on learning and memory in diabetic rats using passive avoidance and Y-maze tests. As a conclusion, it was suggested that Apium graveolens enhances the consolidation and recall capability of stored information in diabetic animals [7]. Zingiber officinale has been used in type II diabetes mellitus [8-11]. Thomson et al. study shows that Allium sativum has anti-diabetic and hypolipidemic properties in streptozotocin-induced diabetic rats [12]. According to one study, it has been determined that the Withania somnifera root and leaf extracts possess antidiabetic activities in alloxan-induced diabetic rats. Withania somnifera root extract contained more flavonoids than leaf extract [13]. In one study, the hypoglycemic effect of the rhizomes of Smilax glabra (Liliaceae) was investigated in normal and diabetic mice. The methanol extract of Smilax glabra reduced the blood glucose of normal mice and also significantly lowered the blood glucose of diabetic mice. This study shows that Smilax glabra has hypoglycemic effect [14]. The discovery and use of modern medicine led to a dramatic decline in the occurrence of diseases. The harmful toxic effects of synthetic drugs


Introduction
Type II diabetes mellitus is a clinical syndrome due to relative or absolute deficiency of insulin or resistance to the action of insulin at the cellular level as a result hyperglycemia and glycosuria occurs [1]. Various new therapies have been introduced such as inhibition of enzymes that are involved in hydrolysis of dietary polysaccharides in the gut which can lead to reduction in blood glucose levels after a meal by reducing the absorption of monosaccharide by the entrecotes of the small intestine. Enzymes that are involved in hydrolysis of dietary polysaccharides are pancreatic amylase and glycosidase. With the advancement in treatment strategy there is risk of side effect such as excessive inhibition of pancreatic amylase may lead to abdominal distention, flatulence and diarrhea. Currently available therapies for type II diabetes mellitus are as follows oral insulin secretagogues, sulfonylureas, repaglinide, nateglinide, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, insulin, pramlintide and exenatide. Oral hypoglycemic drugs are valuable in the treatment of patients with type II diabetes mellitus (NIDDM). Sulphonylureas and biguanides are traditional drugs which are mainstay of treatment while there are certain new drugs available now [2,3]. Insulin is used as hypoglycemic agent in Type II diabetes mellitus [4]. The use of herbal medicines (medicinal plants or phytotherapy) has recently gained popularity in all over the world for their efficacy in Type II diabetes mellitus (Table  1) and some plants have minor side effects when given in large doses (Table 2). But there is lack of understanding the actual mechanism of action of these medicines. These medicines are used since centuries in Unani system of medicine and they have more efficacy and fewer or no side effects therefore emphasis should be given on herbal medicine because allopathic system of medicine has failed in providing health to all. Herbal medicines are only alternative medicine that can relieve the patients. Various research studies have been carried in all over the world to evaluate the efficacy of herbs in the treatment of Type II diabetes mellitus [5]. Medicinal plants have been used for the treatment of type II diabetes mellitus since ancient times, and for a long time type II diabetes mellitus has been treated orally with herbal medicines or their extracts, because plant products are frequently prescribed due to their less toxicity than conventional medicines. Shanmugam et al. reported medicinal plants used for the treatment of type II diabetes mellitus [6]. Type II diabetes mellitus is associated with disturbances in learning, memory, and cognitive skills in the diabetic patients. A study was conducted to evaluate the effect of chronic intraperitoneal administration of Apium graveolens on learning and memory in diabetic rats using passive avoidance and Y-maze tests. As a conclusion, it was suggested that Apium graveolens enhances the consolidation and recall capability of stored information in diabetic animals [7]. Zingiber officinale has been used in type II diabetes mellitus [8][9][10][11]. Thomson et al. study shows that Allium sativum has anti-diabetic and hypolipidemic properties in streptozotocin-induced diabetic rats [12]. According to one study, it has been determined that the Withania somnifera root and leaf extracts possess antidiabetic activities in alloxan-induced diabetic rats. Withania somnifera root extract contained more flavonoids than leaf extract [13]. In one study, the hypoglycemic effect of the rhizomes of Smilax glabra (Liliaceae) was investigated in normal and diabetic mice. The methanol extract of Smilax glabra reduced the blood glucose of normal mice and also significantly lowered the blood glucose of diabetic mice. This study shows that Smilax glabra has hypoglycemic effect [14]. The discovery and use of modern medicine led to a dramatic decline in the occurrence of diseases. The harmful toxic effects of synthetic drugs

Gymnema sylvestre
When chewed, it temporarily paralyses the sense of taste for sweet and bitter substances 3-7 grams

Ficus bengalensis
It may cause harmful effects on stomach and intestine 3-5 grams Table: 2 Side effects in human and dose [101].
led to alternative sources which would be safe and effective in various diseases. The present study is to document the medicinal plants used in type II diabetes mellitus.

Materials and Methods
The material for this review was taken mostly from endocrinology textbooks & electronic journal Up to date. To collect publication Pub Med, Google scholars and the Cochrane database of systematic reviews was used. Some other relevant references were collected from personal database of papers on type II diabetes mellitus.

New drugs for NIDDM
These include insulin sensitizers, drugs which reduce insulin resistance by interaction with the PPAR-(peroxisome proliferatorsactivated receptor-) a nuclear receptor which regulates genes involved in lipid metabolism. The effect on insulin sensitivity may result from decreased production of nonesterified fatty acids. They have the capacity to potentiate the effect of endogenous insulin. One of these, troglitazone, which belongs to the thiazolidinedione group, is used in Type II diabetes mellitus. Repaglinide, a benzoic acid derivation which stimulates insulin production at meal times has been used in type II diabetes mellitus patients [17].

DPP-4 inhibitors:
Drugs targeting the incretin pathway are the latest addition to the available antidiabetic agents. Incretin-based therapy is either delivered orally (dipeptidyl peptidase-4 [DPP-4]) inhibitors or injected subcutaneously (glucagon-like peptide-1 [GLP-1] mimetics and analogues). Dipeptidyl peptidase-4 inhibitors are effective either as a single or combination therapy in lowering glycated hemoglobin, fasting and postprandial glucose levels, with a low incidence of hypoglycemia and no weight gain. There are 3 DPP-4 inhibitors currently available (sitagliptin, saxagliptin, and vildagliptin), with more expected to be available in the future. DPP-4 inhibitors are effective in the treatment of patients with type 2 diabetes [18].
Incretin mimetics: Incretin-related therapies offer great potential for the treatment of people with type II diabetes mellitus. Major incretins that affect glucose metabolism are GLP-1: glucagon-like peptide-1 and GIP: glucose-dependent insulinotropic polypeptide. These therapies have a unique mechanism of action that addresses glucose appearance as well as glucose disappearance [19].

Thiazolidinediones:
The thiazolidinediones also known as glitazones, are a class of medications that are used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s [20].

Αlpha glucosidase inhibitors:
One alternative approach o the treatment of overweight patients with NIDDM is to use drugs which inhibit the enzymes involved in the breakdown of carbohydrates in the intestine. Acarbose is a sham sugar that competitively inhibits α-glucosidase enzymes situated on the brush border of the intestine. As a result, dietary carbohydrates are poorly absorbed, and the postprandial rise in blood glucose is reduced. Undigested starch enters the large intestine where it is broken down by fermentation. Abdominal discomfort, flatulence and diarrhea can result, and dosage needs careful adjustment to avoid these side effects. Very little acarbose enters the circulation, since it is mainly inactivated in the gut, but liver dysfunction may rarely occur with high doses [21].

Medicinal Plants Possessing Alpha -Glucosidase Inhibitory Activities
Glycosidases are involved in metabolic disorders including type II diabetes mellitus. Inhibition of these glycosidase may be proved effective in type II diabetes mellitus. Various medicinal plants have been evaluated for their efficacy to inhibit glucosidase. Euonymus sachalinensis, Rhododendron schlippenbachii, Astilbe chinensis and Juglans regia have inhibitory effect on glucosidase, therefore can be a potential natural source for the treatment of type II diabetes mellitus [22].

Tussilago farfara
Family: Asteraceae. Chemical constituents: It contains mucilage, tannin, phytosterol, dihydride alcohol and faradial. Medicinal uses: It is used in catarrh, colds, whooping cough, respiratory problems, spasmodic lung problem, stomach trouble, inflammation and bleeding. Pharmacological activity: It is anti-inflammatory, anti-spasmodic and hypoglycemic. Study: Gao et al. reported the α-glucosidase inhibitory activity of this plant and concluded that flower bud of Tussilago farfara is useful in type II diabetes mellitus [23].

Prinsepia utilis Royle
Family: Rosaceae, Parts used: Aerial parts. Chemical constituents: It contains pentacyclic triterpenoids. Medicinal uses: Oil from seeds is rubifacient and is applied locally in rheumatism. Pharmacological activity: It is anti-inflammatory, anti-arthritic and hypoglycemic. Study: A study was conducted to investigate the anti-hyperglycemic activity of flavonoids from Prinsepia utilis Royle in alloxan-induced diabetic mice. Study duration was four weeks. Drug was administered orally. Dose of drug was 300 mg/kg of flavonoids from Prinsepia utilis Royle. There was significant hypoglycemic activity of Flavonoids from Prinsepia utilis Royle compared with model control group (P<0.01) [24].

Ricinus communis L.
Family: Euphorbiaceae, Common name: Harnoli. Parts used: Root, leave, oil. Chemical constituents: It contains ricinolein, flavonoids, ricin, ricinolic acid, sodium ricinoleate, tristearin. Medicinal uses: It is used in constipation, pain and inflammation. Pharmacological activity: It is anti-inflammatory, laxative and hypoglycemic. Study: Hypoglycemic activity of 50% ethanolic extract of roots of Ricinus communis was investigated. Effective dose was 500 mg/kg body weight. There was significant decrease in fasting blood glucose level. Hypoglycemic activity was observed in normal as well as diabetic animal model. Study duration was 20 days. There was significant reduction in lipid profile and liver and kidney functions were normal during the study period. Fractionation of this extract was done and these were tested for antihyperglycemic activity. Fraction (R-18) exhibited significant hypoglycemic activity. This drug was safe because there was no effect on liver and kidney function and all enzymes were normal [25].

Aloe vera
Family: Xanthorrhoeaeceae, Chemical constituents: It contains anthraquinone glycosides, free anthaquinones, resins, glucomannan, steroids, organic acids, enzymes, antibiotic principles, amino acids, cinnamic acid and salicylic acid, essential oil. Medicinal uses: It is used in inflammation, wounds and bacterial infections. Pharmacological activity: It is soothing, anti-inflammatory, emmengogue, emollient, and antibacterial. Study: Rajasekaran et al. reported the hypoglycemic effect of Aloe vera gel on streptozotocin-induced hyperglycemia in experimental rats [26]. Okyar et al. reported the antidiabetic effect of Aloe vera in type II diabetic rat models [27].

Crataeva nurvala Buch
Family: Capparidaceae. Parts used: Leaves. Chemical constituents: It contains tannin and saponin. Medicinal uses: It is used in diabetes mellitus. Pharmacological activity: It is hypoglycemic. Study: Sikarwar and Patil reported the antidiabetic activity of Crateva nurvala stem bark extracts in alloxan-induced diabetic rats [28].

Smilax chinensis
Family: Liliaceae, Chemical constituents: It contains beta sitosterol, oil, diosgenin, smilacin, resin, tannin, starch, gum, sarsapogenin, sapogenins, parallin, sarsaponin and saponins. Medicinal uses: It is used in inflammation, cancer and type II diabetes mellitus. Pharmacological activity: It is anti-inflammatory and anti-diabetic. Study: The antidiabetic effects of the methanol extracts of the Smilax chinensis L. (MESC) on alloxan induced hyperglycemia were evaluated on albino wistar rats. Ethanolic extract of Smilax chinensis exhibited potential hypoglycemic effect with potential hypolipidemic effect (Venkidesh et al. 2010) [31]. The anti-diabetic effects of the methanol extracts of the Smilax chinensis L. on alloxan induced hyperglycemia were evaluated on albino wistar rats. Ethanolic extract of Smilax chinensis exhibited a potential hypoglycemic effect with potential hypolipidemic effect [32].

Urginea indica
Family: Liliaceae. Tibbi name: Jangli Piyaz. Chemical constituents: It contains glycosides, scillaren A and scillaren B. Medicinal uses: It is used in urinary tract infections and type II diabetes mellitus. Pharmacological activity: It is anti-septic and hypoglycemic. Study: The extract of this plant has hypoglycemic activity [34].

Acacia nilotica
Family: Fabaceae; Local name: Kikar; Parts used: Wood, leave and gum. Chemical constituents: It contains gum arabic, tannins, mucilage, magnesium, potassium, calcium, catechin, arabic acid, malic acid and flavonoid compounds. Medicinal uses: It is prescribed for treatment of type II diabetes mellitus. Pharmacological activity: It is astringent and hypoglycemic. Study: Usmanghani et al. documented its anti-diabetic activity [35].

Achyranthes aspera
Family: Amaranthaceae; Parts used: Leaves, stems and roots. Chemical constituents: Saponins, ecdysterone, inokosterone, achyranthine, and potassium, ash of leaves, stems and root contains considerable amount of potassium. Medicinal uses: It is used in diabetes mellitus. Pharmacological activity: It is hypoglycemic. Study: A study was conducted to evaluate its efficacy in diabetic rat. Alcoholic extract of whole plant was given to albino rat. Alcoholic extract exhibited hypoglycemic activity in albino rats [36].

Luffa aegyptiaca Mill
Family: Cucurbitaceae; Medicinal uses: It is used in joint pain, backache, colic, splenitis and phlegmatic diseases. Pharmacological activity: It is anti-inflammatory and hypoglycemic. Study: El-Fiky et al. investigated the efficacy of oral administration of the ethanolic extracts of Luffa aegyptiaca on blood glucose levels both in normal and streptozotocin diabetic rats. Hypoglycemic activity was observed significantly in streptozocin diabetic rats during the first three hours of treatment. In normal rats, hypoglycemic activity was insignificant compared to glibenclamide treatment [37].

Citrus paradisi
Family: Rutaceae; Medicinal uses: It is used in diabetes mellitus type II and bacterial infections. Pharmacological activity: Antibacterial and hypoglycemic. Study: Adeneye reported that methanol seed extract of Citrus paradisi lowers blood glucose, lipids and cardiovascular disease risk indices in normal Wistar rats [38].

Aegle marmelos
Family: Rutaceae; Part used: Fruits, leaves. Medicinal uses: It is used in chronic constipation, piles, dysentery, hyperacidity, abdominal pain and type II diabetes mellitus. Pharmacological activity: It is mucilaginous, antidiabetic and antidysentric. Study: A study was conducted on normal and diabetic rats. Fruit of this plant exhibited hypoglycemic activity in normal rats [39]. Family: Cucurbitacea. Common name: Jangli Kareela. Parts used: Fruit and seeds. Chemical constituents: It contains vitamin C and momorcidin. Medicinal uses: It is used in type II diabetes mellitus, gas trouble, constipation, flatulence, obesity, boils and pimples. Pharmacological activity: It is hypoglycemic, stomachic and blood purifier. Study: Leung et al. stated its anti-diabetic and hypoglycemic activity [41].

Morus alba L.
Family: Moraceae. Common name: Shehtoot, Parts used: Leave, fruit. Chemical constituents: It contains polyphenol pigment, anthocyanins, resveratrol, vitamin C, carotene, zea xanthin, iron, magnesium, manganese and potassium. Medicinal uses: It is used in sore throat, cough and abdominal worms. Pharmacological activity: It is anthelmintic and hypoglycemic. Study: Mohammadi and Naik reported the hypoglycemic activity and are prescribed to treat diabetes mellitus type II [44].

Aerva lanata
Chemical constituents: It contains galactoside and kampferol. Medicinal uses: It is used in kidney stones, constipation and diabetes mellitus type II. Pharmacological activity: Diuretic, purgative, emetic and hypoglycemic. Study: Vetrichelvan and Jegadeesan reported the anti-diabetic activity of alcoholic extract of Aerva lanata in rats and concluded that this plant can be prescribed to treat diabetes mellitus type II [45].

Ginkgo biloba
Family: Ginkgoaceae. Chemical constituents: It contains flavonoids and terpenoids. Medicinal uses: It is used in dementia, intermittent claudication, anxiety, glaucoma, macular degewneration, premenstrual syndrome, cardiovascular disorders and diabetes mellitus type II. Pharmacological activity: It is hypoglycemic and antioxidant. Study: Chen et al. reported that Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redoxdependent interleukin-6 pathways [49].

Allium cepa L.
Local name: Kashuh, Parts used: Leaves and bulbs. Chemical constituents: It contains phytoncides, vitamins, allicin, flavonoids, allylpropyl disulfide, essential oil, quercetin, scordine and fatty oil. Medicinal uses: It is used in ear pains, flatulence and skin diseases. Pharmacological activity: It is aphrodisiac and hypoglycemic. Study: Mathew and Augusti reported the hypoglycemic activity of Allium cepa and concluded that this plant can be prescribed to treat type II diabetes mellitus [51].

Ajugaiva L
Family: Lamiaceae. Medicinal uses: It is used in diabetes mellitus type II. Pharmacological activity: It is hypoglycemic. Study: A study was conducted to investigate the hypoglycemic activity of Ajuga iva L. in rat model. This plant is commonly available in Asia and Africa. Water extract of Ajuga iva L (AT) was administered to rats at a dose of 10 mg/ kg that reduced blood glucose level in rats 6 hours. This study indicates that Ajuga iva L. has hypoglycemic activity and validates its traditional use in hyperglycemic conditions [64].

Tribulus terrestris
Family: Zygophyllaceae. Medicinal uses: It is used in urinary tract infection and type II diabetes mellitus [65]. Pharmacological activity: It is diuretic, lithotriptic, anti-inflammatory and hypoglycemic. Study: A study was conducted to evaluate the efficacy of Tribulus terrestris in alloxan induced diabetic rats. After treatment, it was concluded that Tribulus terrestris has prominent antidiabetic effect [66].

Anacardium occidentale linn
Family: Anacardiacea, Part used: Leaves and fruit. Medicinal uses: It is used in diabetes mellitus type II. Pharmacological activity: It is anti-diabetic. Study: Ojewole reported the hypoglycemic effect of Anacardium occidentale Linn (Anacardiaceae) stem-bark extracts in rats [67].

Bougainvillea glabra
Family: Nyctaginaceae, Parts used: Leaves, flowers and stems. Chemical constituents: It contains alkaloids, flavonoids, pinitol and betacynin. Medicinal uses: It is used in inflammation and diabetes mellitus type II. Pharmacological activity: It is anti-inflammatory, insecticidal and hypoglycemic. Study: Bhat et al. reported the antidiabetic properties of Bougainvillea spectabilis. This study justifies its use as herbal drug in type II diabetes mellitus [68].

Conclusion
Many herbs and plants have been described as possessing hypoglycemic activity when taken orally. Some of these plants have also been pharmacologically tested and shown to be of some value in human type II diabetes mellitus treatment. The efficacy of herbal drugs is significant and they have fewer side effects than the synthetic allopathic medicines. Further, phytochemical characterization of medicinal plants is required to identify the specific compound(s) involved in the observed hypoglycemic.

Disclosure Statement
None of the authors have a financial or proprietary interest in the subject matter or materials discussed in the manuscript, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.